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WO2007058194A1 - Inhibiteur de l'induction des cellules t cytotoxiques - Google Patents

Inhibiteur de l'induction des cellules t cytotoxiques Download PDF

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Publication number
WO2007058194A1
WO2007058194A1 PCT/JP2006/322726 JP2006322726W WO2007058194A1 WO 2007058194 A1 WO2007058194 A1 WO 2007058194A1 JP 2006322726 W JP2006322726 W JP 2006322726W WO 2007058194 A1 WO2007058194 A1 WO 2007058194A1
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WO
WIPO (PCT)
Prior art keywords
antibody
inhibitor
receptor
cytotoxic
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2006/322726
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English (en)
Japanese (ja)
Inventor
Masaji Okada
Masafumi Takahashi
Atsushi Izawa
Yoshiyuki Ohsugi
Masahiko Mihara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Shinshu University NUC
National Hospital Organization
Original Assignee
Chugai Pharmaceutical Co Ltd
Shinshu University NUC
National Hospital Organization
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd, Shinshu University NUC, National Hospital Organization filed Critical Chugai Pharmaceutical Co Ltd
Priority to US12/085,065 priority Critical patent/US8623355B2/en
Priority to KR1020087014199A priority patent/KR101457709B1/ko
Priority to JP2007545256A priority patent/JP5189366B2/ja
Priority to EP06832657.8A priority patent/EP1967207B1/fr
Publication of WO2007058194A1 publication Critical patent/WO2007058194A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/248—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a cytotoxic T cell (killer T cell) induction inhibitor containing an IL-6 inhibitor as an active ingredient, and use thereof.
  • the present invention also relates to a method for suppressing rejection after transplantation, which comprises the step of administering an IL-6 inhibitor to a subject.
  • IL-6 is a cytodynamic force also called B cell stimulating factor 2 (BSF2) or interferon ⁇ 2.
  • BSF2 B cell stimulating factor 2
  • IL-6 was discovered as a differentiation factor involved in the activation of vaginal lymphoid cells (Non-patent Document 1), and it was later revealed that it is a multifunctional site force-in that affects the functions of various cells. (Non-Patent Document 2).
  • IL-6 has been reported to induce maturation of vaginal lymphoid cells (Non-patent Document 3).
  • IL-6 transmits its biological activity via two proteins on cells.
  • One is IL-6 receptor, a ligand-binding protein with a molecular weight of about 80 kD to which IL-6 binds (Non-patent Documents 4 and 5).
  • IL-6 receptor exists as a soluble IL-6 receptor mainly composed of an extracellular region in addition to a membrane-bound type that penetrates the cell membrane and is expressed on the cell membrane.
  • the other is a membrane protein gpl30 having a molecular weight of about 130 kD involved in non-ligand binding signal transduction.
  • IL-6 and IL-6 receptor form an IL-6ZIL-6 receptor complex, and then bind to gpl30, thereby transmitting the biological activity of IL-6 into the cell (Non-Patent Literature) 6).
  • IL-6 inhibitors are substances that inhibit the transmission of biological activities of IL-6. So far, antibodies against IL-6 (anti-IL-6 antibody), antibodies against IL-6 receptor (anti-IL-6 receptor antibody), antibodies against gpl 30 (anti-gpl30 antibody), IL-6 variants, IL-6 or IL-6 receptor partial peptides are known.
  • Non-patent Documents 7 and 8, Patent Documents 1 to 3 There are several reports regarding anti-IL-6 receptor antibodies (Non-patent Documents 7 and 8, Patent Documents 1 to 3).
  • One such antibody is the human rabbit PM-1 antibody obtained by transplanting the complementarity determining region (CDR) of mouse antibody PM-1 (Non-patent Document 9) into a human antibody.
  • Patent Document 4 IL-6 is known to be involved in the induction of cytotoxic sputum cells as a killer T cell activity factor (KHF) (Non-patent Document 10).
  • KHF killer T cell activity factor
  • rIL-6 induced cytotoxic T cell differentiation from human peripheral blood T cells and CD4-8- or CD4-8 + thymic T cells in the presence of IL-2. Induced.
  • IL-6 is known to act as a differentiation inducer of cytotoxic T cells in vivo (Non-patent Document 11).
  • Non-patent literature l Hirano, T. et al, Nature (1986) 324, 73-76
  • Non-Patent Document 2 Akira, S. et al., Adv. In Immunology (1993) 54, 1-78
  • Non-Patent Document 3 Lotz, M. et al "J. Exp. Med. (1988) 167, 1253-1258
  • Non-Patent Document 4 Taga, T. et al "J. Exp. Med. (1987) 166, 967-981
  • Non-Patent Document 5 Yamasaki, K. et al., Science (1988) 241, 825-828
  • Non-Patent Document 6 Taga, T. et al "Cell (1989) 58, 573-581
  • Non-Patent Document 7 Novick, D. et al., Hybridoma (1991) 10, 137-146
  • Non-Patent Document 8 Huang, Y. W. et al., Hybridoma (1993) 12, 621-630
  • Non-Patent Document 9 Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906
  • Non-Patent Document 10 Okada M. et al., J. Immunology 141: 1543-1549, 1988
  • Non-Patent Document l l Kitahara M. et al, Jpn. J. Cancer Res. 81: 1032- 1038.1990
  • Patent Document 1 International Patent Application Publication Number WO 95-09873
  • Patent Document 2 French Patent Application Publication Number FR 2694767
  • Patent Document 3 US Patent No.US 5216128
  • Patent Document 4 International Patent Application Publication Number WO 92-19759
  • the present inventors have examined the inhibitory effect of anti-IL-6 receptor antibody on the induction of cytotoxic T cells.
  • the present inventors administered P815 mastocytoma cells intraperitoneally to C57BL / 6 mice.
  • EL4 lymphoma cells were intraperitoneally administered to BALB / c mice as immune cells (allogeneic antigen). Spleens are collected from these mice, and spleen cells (effector cells) are used as the target immune cells and cultured at various effector cell / target cell (E / T) ratios. Activity (cytotoxic T cell activity) was measured.
  • anti-IL-6 receptor antibody or rat HgG control antibody
  • mice treated with anti-IL-6 receptor antibody showed statistically significant CTL activity against allogeneic antigens compared to mice not treated with antibody and mice treated with control antibody. ( Figures 1-4). From the above results, it was revealed that the anti-IL-6 receptor antibody has the function of suppressing the induction of cytotoxic T cells.
  • the present inventors examined the administration effect of anti-IL-6 receptor antibody in an allogeneic mouse heart transplantation model.
  • administration of anti-IL-6 receptor antibody suppressed the acute rejection of the transplanted heart and statistically significantly prolonged the survival time of the transplanted heart.
  • 5 days after transplantation the transplanted heart was removed from the recipient and subjected to histopathological examination.
  • the anti-IL-6 receptor antibody treatment group inflammatory cell infiltration into the transplanted cardiac tissue was significantly suppressed.
  • the construction of cardiomyocytes was relatively maintained.
  • the present inventors show that administration of an anti-IL-6 receptor antibody can suppress the induction of cytotoxic T cells and suppress rejection after transplantation. For the first time, the present invention has been completed.
  • the present invention provides the following [1] to [46].
  • a cytotoxic T cell induction inhibitor comprising an IL-6 inhibitor as an active ingredient.
  • An inhibitor of rejection in heart transplantation comprising an IL-6 inhibitor as an active ingredient.
  • an inhibitor of rejection in heart transplant according to [9] wherein the IL-6 inhibitor is an antibody that recognizes IL-6.
  • [17] A method for suppressing the induction of cytotoxic T cells, comprising a step of administering an IL-6 inhibitor to a subject [18] The method of [17], wherein the IL-6 inhibitor is an antibody that recognizes IL-6. [19] The method according to [17], wherein the IL-6 inhibitor is an antibody that recognizes an IL-6 receptor.
  • [30] Use according to [26] or [27], wherein the antibody is a recombinant antibody.
  • the antibody is a chimeric antibody, a humanized antibody or a human antibody.
  • a method for suppressing rejection in heart transplantation comprising a step of administering an IL-6 inhibitor to a subject.
  • IL-6 inhibitor for producing an inhibitor of rejection in heart transplantation.
  • the IL-6 inhibitor is an antibody that recognizes IL-6.
  • the IL-6 inhibitor is an antibody recognizing IL-6 receptor.
  • FIG. 1 Specific cytotoxic activity at each E / T ratio (CTL activity) in non-antibody-treated mice, anti-IL-6 receptor antibody-treated mice, and control antibody-treated mice treated with P815 mastocytoma cells
  • FIG. 2 Specific cytotoxic activity at 100 E / T ratio in non-antibody-treated mice, anti-IL-6 receptor antibody-treated mice, and control antibody-treated mice treated with P815 mastocytoma cells ( (CTL activity).
  • FIG. 3 Specific cytotoxic activity at each E / T ratio in non-antibody-treated mice, anti-IL-6 receptor antibody-treated mice, and control antibody-treated mice treated with EL4 lymphoma cells
  • FIG. 6 shows (CTL activity).
  • FIG. 4 Specific cytotoxic activity at an E / T ratio of 400 in non-antibody mice, anti-IL-6 receptor antibody-treated mice, and control antibody-treated mice treated with EL4 lymphoma cells ( (CTL activity).
  • FIG. 5 is a graph showing the engraftment rate of transplanted hearts in an anti-IL-6 receptor antibody treatment group and an untreated group in a mouse heart transplantation model.
  • FIG. 6 is a photograph showing the pathological tissue of the transplanted heart 5 days after transplantation in the anti-IL-6 receptor antibody treatment group and the non-treatment group in a mouse heart transplantation model.
  • FIG. 7 is a diagram showing the results of a comparative examination of transplant heart rejection scores at 5 days after transplantation in an anti-IL-6 receptor antibody treatment group and a non-treatment group in a mouse heart transplant model.
  • the present inventors have found that administration of an anti-IL-6 receptor antibody can suppress the induction of cytotoxic T cells.
  • the present invention is based on these findings.
  • the present invention relates to an inhibitor of cytotoxic T cell induction containing an IL-6 inhibitor as an active ingredient.
  • an “IL-6 inhibitor” is a substance that blocks IL-6 signal transduction and inhibits IL-6 biological activity.
  • the IL-6 inhibitor is preferably a substance having an inhibitory action on binding of any of IL-6, IL-6 receptor and gpl30.
  • Examples of the IL-6 inhibitor of the present invention include an anti-IL-6 antibody, an anti-IL-6 receptor antibody, an anti-gpl30 antibody, an IL-6 variant, a soluble IL-6 receptor variant or an IL. -6 or IL-6 receptor partial peptides and low molecular weight substances exhibiting the same activity as these, but are not particularly limited.
  • the IL-6 inhibitor of the present invention is preferably an antibody that recognizes IL-6 receptor.
  • the origin of the antibody in the present invention is not particularly limited, but is preferably derived from a mammal, more preferably a human-derived antibody.
  • the anti-IL-6 antibody used in the present invention can be obtained as a polyclonal or monoclonal antibody using known means.
  • anti-IL-6 antibodies used in the present invention Preferred are monoclonal antibodies derived from mammals. Mammal-derived monoclonal antibodies include those produced by hyperpridoma and those produced by a host transformed with an expression vector containing an antibody gene by genetic engineering techniques. This antibody binds to IL-6, thereby inhibiting the binding of IL-6 to the IL-6 receptor and blocking the intracellular transmission of IL-6 biological activity.
  • Such antibodies include MH166 (Matsuda, T. et al., Eur. J. Immunol. (1988) 18, 95 1-956) and SK2 antibody (Sato, K. et al, 21st). The Japanese Society for Immunology General Assembly, academic records (1991) 21, 166) and the like.
  • An anti-IL-6 antibody-producing hyperpridoma can be basically produced using a known technique as follows. That is, using IL-6 as a sensitizing antigen and immunizing it according to the usual immunization method, the obtained immune cells are fused with known parental cells by the usual cell fusion method, and by the usual screening method, It can be produced by screening monoclonal antibody-producing cells.
  • the anti-IL-6 antibody can be prepared as follows.
  • HI-6 used as a sensitizing antigen for antibody acquisition is Eur. J. Biochem (1987) 168, 543-550, J. Im munol. (1988) 140, 1534-1541, or Agr. Biol It is obtained by using the IL-6 gene Z amino acid sequence disclosed in Chem. (1990) 54, 2685-2688.
  • the target IL-6 protein is known from the host cell or culture supernatant.
  • the purified IL-6 protein can be used as a sensitizing antigen.
  • a fusion protein of IL-6 protein and other proteins may be used as a sensitizing antigen!
  • the anti-IL-6 receptor antibody used in the present invention can be obtained as a polyclonal or monoclonal antibody using known means.
  • a monoclonal antibody derived from a mammal is particularly preferable.
  • Monoclonal antibodies derived from mammals include those produced by hyperpridoma and those produced by a host transformed with an expression vector containing an antibody gene by genetic engineering techniques. This antibody binds to the IL-6 receptor, thereby blocking the binding of IL-6 to the IL-6 receptor and blocking the transmission of IL-6 biological activity into the cell.
  • Examples of such antibodies include MR16-1 antibody (Tamura, T. et al. Proc. Natl. Acad. Sci.
  • PM-1 antibody Hirata, Y et al "J. Immunol. (1989) 143, 2 900-2906), AUK12-20 antibody, AUK64-7 antibody or AUK146-15 antibody (International Patent Application Publication No. WO 92-19759).
  • PM-1 antibody is exemplified as a preferred monoclonal antibody against HL-6 receptor
  • MR16-1 antibody is exemplified as a preferred monoclonal antibody against mouse IL-6 receptor. It is done.
  • Anti-IL-6 receptor monoclonal antibody-producing hybridomas and hybridomas can basically be prepared as follows using known techniques. That is, IL-6 receptor is used as a sensitizing antigen and immunized according to a normal immunization method, and the resulting immune cells are fused with a known parent cell by a normal cell fusion method. Thus, a monoclonal antibody-producing cell can be screened.
  • the anti-IL-6 receptor antibody can be prepared as follows.
  • the human HL-6 receptor used as a sensitizing antigen for obtaining an antibody is disclosed in European Patent Application Publication No. EP 3 25474, and the mouse IL-6 receptor is disclosed in Japanese Patent Application Publication No. JP-A 3-155795.
  • the obtained IL-6 receptor gene Z amino acid sequence is used.
  • IL-6 receptor protein is expressed on the cell membrane and detached from the cell membrane
  • Soluble IL-6 receptor (Soluble IL-6 receptor) (Yasukawa, K. et al., J. Biochem. (1990) 108, 673-676). Soluble IL-6 receptor binds to the cell membrane and is composed essentially of the extracellular region of IL-6 receptor, lacking the transmembrane region or the transmembrane region and the intracellular region. It differs from membrane-bound IL-6 receptor in that respect. As long as the IL-6 receptor protein can be used as a sensitizing antigen for the production of the anti-IL-6 receptor antibody used in the present invention, V, a misaligned IL-6 receptor may be used.
  • An IL-6 receptor gene sequence is inserted into a known expression vector system to transform an appropriate host cell, and then the target IL-6 receptor is obtained from the host cell or culture supernatant.
  • the protein may be purified by a known method, and this purified IL-6 receptor protein may be used as a sensitizing antigen. Further, cells expressing IL-6 receptor or a fusion protein of IL-6 receptor protein and other proteins may be used as the sensitizing antigen.
  • the anti-gpl30 antibody used in the present invention may be polyclonal or monoclonal using known means. It can be obtained as a clonal antibody.
  • Anti g P 130 antibody used in the present invention preferably monoclonal antibodies derived from mammals are especially.
  • Mammal-derived monoclonal antibodies include those produced by hyperpridoma and those produced by a host transformed with an expression vector containing an antibody gene by genetic engineering techniques. This antibody binds to gpl30, thereby inhibiting the binding of IL-6ZIL-6 receptor complex to gpl30 and blocking the transmission of IL-6 biological activity into the cell.
  • Examples of such antibodies include the ⁇ 164 antibody (Japanese Patent Laid-open No. 3-219894), 4811 antibody chobi 21 "[4 antibody (US 5571513) B-S12 antibody and B-P8 antibody (Japanese Patent Laid-Open No. 8-291199). Can be mentioned.
  • the anti-gpl30 monoclonal antibody-producing hybridoma ibridoma
  • gpl30 is used as a sensitizing antigen and immunized according to the usual immunization method.
  • the obtained immune cells are fused with known parental cells by the usual cell fusion method, and then monoclonal by the usual screening method. It can be produced by screening antibody-producing cells.
  • a monoclonal antibody can be prepared as follows.
  • gpl30 used as a sensitizing antigen for obtaining an antibody can be obtained by using the gpl30 gene Z amino acid sequence disclosed in European Patent Application Publication No. EP 411946.
  • the target gpl30 protein is obtained from the host cell or culture supernatant by a known method.
  • the purified gpl30 protein may be purified and used as a sensitizing antigen.
  • cells expressing gpl30 or a fusion protein of gpl30 protein and other proteins may be used as the sensitizing antigen.
  • the mammal to be immunized with the sensitizing antigen is not particularly limited, but it is generally preferable to select in consideration of compatibility with the parent cell used for cell fusion.
  • Rodent animals such as mice, rats, hamsters and the like are used.
  • the animal is immunized with the sensitizing antigen according to a known method.
  • a sensitizing antigen is injected intraperitoneally or subcutaneously into a mammal.
  • the sensitizing antigen is diluted to an appropriate amount with PBS (Phosphate-Buffered Saline) or physiological saline and suspended, and a conventional adjuvant such as Freund's is used if desired.
  • PBS Phosphate-Buffered Saline
  • physiological saline physiological saline
  • a conventional adjuvant such as Freund's
  • an appropriate carrier can be used during immunization with the sensitizing antigen.
  • immune cells are removed from the mammal and subjected to cell fusion.
  • Preferred immune cells that are subjected to cell fusion include spleen cells.
  • Mammalian myeloma cells as the other parental cells to be fused with the immune cells are already known in various cell lines such as P3X63Ag8.653 (Kearney, JF et al. J. Imm unol. 1979) 123, 1548-1550), P3X63Ag8U.l (Current Topics in Microbiology and Immunology (1978) 81, 1-7), NS-1 (Kohler. G. and Milstein, C. Eur. J. Immunol. (19 76) 6, 511-519), MPC-11 (Margulies. DH et al "Cell (1976) 8, 405-415), SP2 / 0 (Shulman, M.
  • the cell fusion between the immunocytes and myeloma cells is basically performed by a known method, for example, the method of Milsteina et al. (Kohler. G. and Milstein, C., Methods Enzymol. (1981) 73, 3 -46 ) And the like.
  • the cell fusion is performed, for example, in a normal culture medium in the presence of a cell fusion promoter.
  • a cell fusion promoter for example, polyethylene glycol (PEG), Sendai virus (HVJ) or the like is used as a fusion promoter, and an auxiliary agent such as dimethyl sulfoxide may be added and used to increase the fusion efficiency as desired.
  • the use ratio of immune cells and myeloma cells is preferably 1 to 10 times the number of immune cells relative to myeloma cells, for example.
  • the culture medium used for the cell fusion for example, RPMI1640 culture medium suitable for the growth of the myeloma cell line, MEM culture medium, and other normal culture liquids used for this type of cell culture can be used.
  • serum supplements such as fetal calf serum (FCS) can be used in combination.
  • a predetermined amount of the immune cells and myeloma cells are mixed well in the culture solution and pre-warmed to about 37 ° C, for example, an average molecular weight of about 1000 to 6000.
  • PEG solution is usually added at a concentration of 30 to 60% (w / v) and mixed to form the desired fused cell (hybridoma).
  • cell fusion agents and the like unfavorable for the growth of hypridoma can be removed by repeating the operation of adding an appropriate culture solution successively, centrifuging and removing the supernatant.
  • the above-mentioned ibridoma is selected by culturing in a normal selective culture solution, for example, a HAT culture solution (a culture solution containing hypoxanthine, aminopterin and thymidine). Culturing with the HAT medium is continued for a period of time, usually several days to several weeks, sufficient for the cells (non-fusion cells) other than the target hyperpridoma to die. Then, the usual limiting dilution method is performed, and the screening and cloning of the hyperidoma producing the target antibody is performed.
  • a normal selective culture solution for example, a HAT culture solution (a culture solution containing hypoxanthine, aminopterin and thymidine). Culturing with the HAT medium is continued for a period of time, usually several days to several weeks, sufficient for the cells (non-fusion cells) other than the target hyperpridoma to die. Then, the usual limiting dilution method is performed, and the screening and cloning of the
  • human lymphocytes are sensitized with a desired antigen protein or antigen-expressing cells in vitro, and sensitized B lymphocytes are human myeloma. It is also possible to obtain a desired human antibody having a binding activity to a desired antigen or antigen-expressing cell by fusing with a cell such as U266 (see Japanese Patent Publication No. 59878). Furthermore, an antigen or an antigen-expressing cell may be administered to a transgenic animal having a repertoire of human antibody genes, and a desired human antibody may be obtained according to the method described above. (International Patent Application Publication Number) WO 93/12227, WO 92/03918, WO 94/02602, WO 94/25585, WO 96/34096, WO 96/33735).
  • the thus-produced monoclonal antibody and hybridoma can be subcultured in a normal culture solution, and can be stored for a long time in liquid nitrogen. .
  • the hybridoma can be obtained by culturing the hyperidoma according to a normal method and obtaining it as a culture supernatant, or administering the hyperidoma to a mammal compatible therewith. Then, it can be proliferated and used as its ascites.
  • the former method is suitable for obtaining high-purity antibodies, while the latter method is suitable for mass production of antibodies.
  • the production of anti-IL-6 receptor antibody-producing ibridoma can be performed by the method disclosed in JP-A-3-139293.
  • PM-1 antibody-producing hybridomas were isolated from BALB / c mice. Ascites can be injected into the peritoneal cavity, and PM-1 antibody can be purified from this ascites, or this hybridoma can be added to a suitable medium, such as 10% urine fetal serum, 5% BM-Condimed HI (Boehringer Mannheim Cultured in RPMI1640 medium, Hypridoma SFM medium (GIBCO-BRL), PFPF-PF medium (GIBCO-BRL), etc., and PM-1 antibody is purified from the culture supernatant. it can.
  • a suitable medium such as 10% urine fetal serum, 5% BM-Condimed HI (Boehringer Mannheim Cultured in RPMI1640 medium, Hypridoma SFM medium (GIBCO-BRL), PFPF-PF medium (GIBCO-
  • an antibody gene is cloned by a hybridoma force, incorporated into an appropriate vector, introduced into a host, and produced using a gene recombination technique.
  • Antibodies can be used (see, for example, Borrebaeck CAK and Larrick JW THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).
  • mRNA encoding the variable (V) region of an antibody is isolated from cells producing the antibody of interest, such as Hypridoma. Isolation of mRNA is performed by a known method such as guanidine ultracentrifugation (Chirgwin, JM et al., Biochemistry (1979) 18, 5294-5299), AGPC method (Chomczynski, P. et al., Anal. Prepare total RNA using Biochem. (1987) 162, 156-159), etc., and prepare mRNA using mRNA Purification Kit (Pharmacia). Alternatively, mRNA can be directly prepared using QuickPrep mRNA Purification Kit (Pharmacia).
  • cDNA of the antibody V region is synthesized from the obtained mRNA using reverse transcriptase.
  • cDNA synthesis can be performed using AMV Reverse Transcriptase First-strand cDNA Synthesis Kit or the like.
  • AMV Reverse Transcriptase First-strand cDNA Synthesis Kit or the like.
  • 5'-Ampli FINDER RACE Kit (Clontech) and 5'-RACE method using PCR (Frohman, MA et al., Proc. Natl. A cad. Sci. USA (1988) 85, 8998-9002; Belyavsky, A. et al "Nucleic Acids Res. (1989) l 7, 2919-2932).
  • the desired DNA fragment can be obtained from the obtained PCR product.
  • DNA encoding the V region of the target antibody is obtained, it is ligated to DNA encoding the desired antibody constant region (C region) and incorporated into an expression vector. Or antibody Insert the DNA encoding the V region into an expression vector containing the DNA of the antibody C region.
  • the antibody gene is incorporated into an expression vector so as to be expressed under the control of an expression control region, for example, an enhancer or promoter, as described below.
  • an expression control region for example, an enhancer or promoter, as described below.
  • host cells can be transformed with this expression vector to express the antibody.
  • a genetically modified antibody artificially modified for the purpose of reducing the heterologous antigenicity to humans such as a chimeric antibody, a humanized antibody, a human (human) antibodies
  • modified antibodies can be produced using known methods.
  • a chimeric antibody is produced by ligating the DNA encoding the antibody V region obtained as described above with the DNA encoding the human antibody C region, incorporating it into an expression vector, introducing it into a host, and producing it. (See European patent application publication number EP 125023, international patent application publication number W 0 92-19759). Using this known method, a chimeric antibody useful in the present invention can be obtained.
  • a humanized antibody is also called a reshaped human antibody or a humanized antibody, and a complementarity determining region (CDR) of a mammal other than a human, for example, a mouse antibody, is changed to a complementarity determining region of a human antibody. It is transplanted, and its general gene recombination technique is also known (see European Patent Application Publication No. EP 125023, International Patent Application Publication No. WO 92-19759).
  • a DNA sequence designed to link a CDR of a mouse antibody and a framework region (FR) of a human antibody has a portion that overlaps the terminal portion.
  • Several prepared oligonucleotide forces are also synthesized by PCR.
  • the obtained DNA is obtained by ligating with the DNA encoding the human antibody C region, then incorporating it into an expression vector, introducing it into a host and producing it (European Patent Application Publication Number EP 239400, International Patent Application Publication Number). WO 92-19759).
  • the FR of the human antibody to be ligated via CDR is selected such that the complementarity determining region forms a favorable antigen binding site. If necessary, the framework region of the variable region of the antibody is amino so that the complementarity determining region of the reshaped human antibody forms an appropriate antigen-binding site. Acids may be substituted (Sato, K. et al., Cancer Res. (1993) 53, 851-856).
  • the human antibody C region is used for the chimeric antibody and the humanized antibody.
  • Examples of the human antibody C region include Cy, and for example, C ⁇ 1, C ⁇ 2, C ⁇ 3, or Cy4 can be used.
  • the human antibody C region may be modified in order to improve the stability of the antibody or its production.
  • the chimeric antibody is composed of a variable region of a non-human mammal-derived antibody and a C region derived from a human antibody, and the humanized antibody is a complementarity determining region of a non-human mammal-derived antibody and a frame derived from a human antibody.
  • Both the work region and the C region force are both useful as the antibodies used in the present invention because the antigenicity in the human body is reduced.
  • humanized antibodies used in the present invention include the human PM-1 antibody (see International Patent Application Publication No. WO 92-19759).
  • a technique for obtaining a human antibody by panning using a human antibody library is also known.
  • a variable region of a human antibody can be expressed as a single chain antibody (scFv) on the surface of the phage by the phage display method, and a phage that binds to the antigen can be selected.
  • scFv single chain antibody
  • the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined. If the DNA sequence of scFv that binds to the antigen is clarified, an appropriate expression vector containing the sequence can be prepared, and a human antibody can be obtained.
  • the antibody gene constructed as described above can be expressed by a known method. When mammalian cells are used, they can be expressed by commonly used useful promoters, expressed antibody genes, DNA 3 functionally linked to the 3 'downstream, or vectors containing them. it can.
  • the promoter Zenhansa can be a human cytomegalovirus immediate promoter / enhancer.
  • promoters that can be used for the expression of the antibodies used in the present invention, such as retrovirus, poliovirus, adenovirus, and simian virus 40 (SV40), are also included.
  • Nya Hitchel Longation Factor 1 ⁇ A mammalian cell-derived promoter Zenhancer such as HEFla may be used.
  • promoters include lacZ promoter and & 8 promoter.
  • Ward et al. Ward, ES et al., Nature (1989) 341, 5 44-546; Ward, ES et al. FASEB J. (1992) 6, 2422- 2427
  • araB promoter When using the araB promoter, the method of Better et al. (Better, M. et al. Science (1988) 240, 1041-1043) may be followed.
  • a pelB signal sequence (Lei, S. P. et al J. Bacteriol. (1987) 169, 4379-4383) may be used in the case of production in the periplasm of E. coli. After separating the antibody produced in the periplasm, the structure of the antibody is appropriately refolded and used (see, for example, WO96 / 30394).
  • the vector may include an aminoglycoside phosphotransferase (APH) gene, a thymidine kinase (TK) gene, an E. coli xanthine guanine phosphoribosyltransferase (Ecogpt) gene, a dihydrofolate reductase (dhfr) gene, and the like as selectable markers.
  • APH aminoglycoside phosphotransferase
  • TK thymidine kinase
  • Ecogpt E. coli xanthine guanine phosphoribosyltransferase
  • dhfr dihydrofolate reductase
  • any production system can be used.
  • Production systems for antibody production include in vitro and in vivo production systems.
  • In vitro production systems include production systems that use eukaryotic cells and production systems that use prokaryotic cells.
  • Animal cells include: (1) mammalian cells such as CHO, COS, myeloma, BHK (bab y hamster kidney), HeLa, Vero, etc. (2) Amphibian cells such as Xenopus laevis oocytes, or (3) Insect cells such as s! 9, s! 21, Tn5 etc. .
  • mammalian cells such as CHO, COS, myeloma, BHK (bab y hamster kidney), HeLa, Vero, etc.
  • Amphibian cells such as Xenopus laevis oocytes, or (3) Insect cells such as s! 9, s! 21, Tn5 etc.
  • plant cells cells derived from Nicotiana tabacum are known, and these may be cultured in callus.
  • fungal cells include yeasts such as Saccharomyces birds, row f Saccharomyces cerevisiae, filamentous fungi such as Aspergillus, such as Aspergill us niger, etc.
  • prokaryotic cells When prokaryotic cells are used, there is a production system using bacterial cells.
  • bacterial cells include E. coli and Bacillus subtilis.
  • An antibody can be obtained by introducing a desired antibody gene into these cells by transformation and culturing the transformed cells in vitro. Culture is performed according to a known method. For example, DMEM, MEM, RPMI1640, IMDM can be used as the culture medium, and serum supplements such as fetal calf serum (FCS) can be used in combination. Alternatively, antibodies may be produced in vivo by transferring cells into which the antibody gene has been introduced to the abdominal cavity of animals.
  • examples of in vivo production systems include production systems using animals and production systems using plants.
  • animals When animals are used, there are production systems using mammals and insects.
  • mammals As mammals, goats, pigs, hidges, mice, mice, etc. can be used (Vic ki Glaser, SPECTRUM Biotechnology Applications, 1993).
  • silkworms can be used as insects.
  • tobacco When using a plant, for example, tobacco can be used.
  • An antibody gene is introduced into these animals or plants to produce and recover the antibodies in the body of the animals or plants.
  • an antibody gene is inserted in the middle of a gene encoding a protein produced specifically in milk such as goat j8 casein to prepare a fusion gene.
  • a DNA fragment containing the fusion gene into which the antibody gene is inserted is injected into a goat embryo, and the embryo is introduced into a female goat.
  • hormones may be used as appropriate in the transgenic dog. (Ebert, K.M. et al., Bio / Technology (1994) 12, 699-702;).
  • the baculovirus into which the target antibody gene is inserted is silkworm.
  • the desired antibody gene should be used for plant expression.
  • the vector is inserted into a cluster such as pMON530, and this vector is introduced into a bacterium such as Agrobacterium tumefaciens. This bacterium is infected with tobacco, for example Nicotiana tabacum, and the desired antibody is obtained from the leaves of this tobacco (Julian, K.-C. Ma et al., Eur. J. Immunol. (1994) 24, 131-138) .
  • DNAs encoding the antibody heavy chain (H chain) or light chain (L chain) are separately incorporated into an expression vector. May be transformed simultaneously, or the host may be transformed by incorporating DNA encoding the H and L chains into a single expression vector (see International Patent Application Publication No. WO 94-11523). ).
  • the antibody used in the present invention may be an antibody fragment or a modified product thereof as long as it can be suitably used in the present invention.
  • antibody fragments include Fab, F (ab ′) 2, Fv, or single chain Fv (scFv) in which H chain and L chain Fv are linked by an appropriate linker.
  • the antibody is treated with an enzyme such as papain or pepsin to produce antibody fragments, or genes encoding these antibody fragments are constructed and introduced into an expression vector.
  • an enzyme such as papain or pepsin to produce antibody fragments, or genes encoding these antibody fragments are constructed and introduced into an expression vector.
  • an appropriate host cell eg, Co, MS et al, J. Immunol. (19 94) 152, 2968-2976, Better, M. & Horwitz, AH Methods in Enzymology (1989) 17 8, 476-496 , Plueckthun, A. & Skerra, A. Methods in Enzymology (1989) 178, 497-515, Lamoyi, E., Methods in Enzymology (1989) 121, 652-663, Rousseaux, J. et al., Methods in Enzymology (1989) 121, 663-66, Bird, RE et al., TIBTECH (1991) 9, 132-137).
  • scFv is obtained by linking the H chain V region and L chain V region of an antibody.
  • the H chain V region and the L chain V region are linked via a linker, preferably a peptide linker (Huston, JS et al., Proc. Natl. Acad. Sci. USA (1988). ) 85, 5879—5883).
  • a linker preferably a peptide linker (Huston, JS et al., Proc. Natl. Acad. Sci. USA (1988). ) 85, 5879—5883).
  • the H chain V region and the L chain V region in scFv are described as the above-mentioned antibody, they may be derived from a deviation.
  • the peptide linker that links the V regions for example, any single chain peptide consisting of amino acid residues 12-19 is used.
  • the DNA encoding scFv is composed of a DNA encoding the H chain or H chain V region of the antibody and a DNA encoding the L chain or L chain V region, and the sequence of those sequences.
  • a portion of the DNA encoding the desired amino acid sequence is amplified by PCR using a primer pair that defines both ends of the DNA, and then a DNA encoding a portion of the peptide linker and both ends thereof are respectively H chain, Obtained by combining and amplifying primer pairs that are defined so as to be linked to the L chain.
  • DNA encoding scFv is prepared, an expression vector containing them and a host transformed with the expression vector can be obtained according to a conventional method.
  • ScFv can be obtained according to a conventional method.
  • antibody fragments can be produced by the host by obtaining and expressing the gene in the same manner as described above.
  • antibody as used in the present invention encompasses these antibody fragments.
  • a modified antibody an antibody bound to various molecules such as polyethylene glycol (PEG) can also be used.
  • PEG polyethylene glycol
  • the “antibody” referred to in the present invention includes these modified antibodies. In order to obtain such a modified antibody, it can be obtained by chemically modifying the obtained antibody. These methods are already established in this field.
  • the antibody produced and expressed as described above can be isolated from the inside and outside of the cell and from the host and purified to homogeneity. Separation and purification of the antibody used in the present invention can be carried out by affinity chromatography.
  • Examples of the column used for the affinity chromatography include a protein A column and a protein G column.
  • Examples of the carrier used for the protein A column include HyperD, POROS, Sepharose F.F.
  • the separation and purification methods used for ordinary proteins are not limited in any way.
  • the antibodies used in the present invention can be separated and purified by appropriately selecting and combining chromatography, filters, ultrafiltration, salting out, dialysis and the like other than the above-mentioned affinity chromatography.
  • chromatography include ion exchange chromatography, hydrophobic chromatography, gel filtration, and the like. These chromatograms ⁇ are applied to HPL (High performance liquid chromatography) and protected. You can also use reverse phase HPLC!
  • the antibody concentration obtained above can be measured by measuring absorbance, ELISA, or the like. In other words, when measuring absorbance, after appropriately diluting with PBS (-), measure absorbance at 280 nm and calculate lmg / ml as 1.350D.
  • ELISA it can be measured as follows. That is, 100 ⁇ l of goat anti-HgG (manufactured by TAG) diluted to 1 g / ml with 0.1 M bicarbonate buffer (pH 9.6) was placed in a 96-well plate (manufactured by Nunc) and placed at 4 ° C. -Incubate to immobilize antibody. After blocking, add appropriately diluted antibody to be used in the present invention or a sample containing the antibody, or 100 ⁇ l of HgG (manufactured by CAPPEL) as a sample, and incubate at room temperature for 1 hour.
  • the IL-6 variant used in the present invention is a substance that has binding activity to the IL-6 receptor and does not transmit the biological activity of IL-6. That is, the IL-6 variant does not transmit IL-6 biological activity to the IL-6 receptor competitively with IL-6, and therefore blocks signal transmission by IL-6.
  • the IL-6 variant is produced by introducing a mutation by substituting an amino acid residue in the amino acid sequence of IL-6.
  • the origin of IL-6, which is a variant of IL-6, is not limited, but human IL-6 is preferable in consideration of antigenicity.
  • the amino acid sequence of IL-6 can be determined using a known molecular modeling program such as W HATIF (Vriend et al., J. Mol. Graphics (1990) 8, 52-56). This is done by predicting the next structure and evaluating the effect on the total number of amino acid residues to be substituted. After determining the appropriate replacement amino acid residue, by introducing a mutation that replaces the amino acid by the usual PCR method, using a vector containing the base sequence encoding the HL-6 gene as a saddle type, A gene encoding the IL-6 variant is obtained. This can be incorporated into an appropriate expression vector as necessary, and an IL-6 variant can be obtained according to the expression, production and purification methods of the recombinant antibody.
  • W HATIF Wide et al., J. Mol. Graphics (1990) 8, 52-56
  • IL-6 variants include Brakenhoff et al., J. Biol. Chem. (1994) 269, 86-93. And Savino et al, EMBO J. (1994) 13, 1357-1367, WO 96-18648, W096-17869.
  • the IL-6 partial peptide or IL-6 receptor partial peptide used in the present invention has an IL-6 receptor or IL-6 binding activity, respectively, and the biological activity of IL-6 It is a substance that does not transmit activity. That is, IL-6 partial peptide or IL-6 receptor partial peptide binds to IL-6 receptor or IL-6, and captures these to specifically bind IL-6 to IL-6 receptor. Obstruct it. As a result, IL-6 does not transmit the biological activity of IL-6, thus blocking IL-6 signaling.
  • IL-6 partial peptide or IL-6 receptor partial peptide is a part of a region related to the binding between IL-6 and IL-6 receptor in the amino acid sequence of IL-6 or IL-6 receptor Alternatively, it is a peptide consisting of the entire amino acid sequence. Such peptides usually consist of 10 to 80, preferably 20 to 50, more preferably 20 to 40 amino acid residues.
  • IL-6 partial peptide or IL-6 receptor partial peptide specifies the region involved in the binding of IL-6 to IL-6 receptor in the amino acid sequence of IL-6 or IL-6 receptor Based on the amino acid sequence of a part or all of the specified region, it can be prepared by a generally known method such as a genetic engineering method or a peptide synthesis method.
  • a DNA sequence encoding a desired peptide is incorporated into an expression vector, and expression of the recombinant antibody is performed. It can be obtained according to production and purification methods.
  • a method usually used in peptide synthesis for example, a solid phase synthesis method or a liquid phase synthesis method may be used. it can.
  • a deprotection reaction and a cleavage reaction from the peptide chain support are performed.
  • hydrogen fluoride or trifluoromethanesulfonic acid can usually be used for the Boc method
  • TFA can be used for the Fmoc method.
  • Boc method for example, the protected peptide resin is treated in hydrogen fluoride in the presence of carsol. The peptide is then recovered by removing the protecting group and cleaving the support force. This is freeze-dried to obtain a crude peptide.
  • the deprotection reaction and the cleavage reaction from the peptide chain support can be performed in TFA by the same operation as described above.
  • the obtained crude peptide can be separated and purified by application to HPLC. For elution, use water-acetonitrile solvent usually used for protein purification under optimal conditions. The fraction corresponding to the peak of the obtained chromatographic profile is collected and lyophilized. The peptide fraction thus purified is identified by molecular weight analysis by mass spectrum analysis, amino acid composition analysis, amino acid sequence analysis, or the like.
  • IL-6 partial peptide and IL-6 receptor partial peptide are disclosed in JP-A-2-188600, JP-A-7-324097, JP-A-8-311098 and US Patent Publication US5210075.
  • the antibody used in the present invention may be a conjugated antibody bound to various molecules such as polyethylene glycol (PEG), radioactive substances, and toxins.
  • PEG polyethylene glycol
  • Such a conjugated antibody can be obtained by chemically modifying the obtained antibody.
  • Antibody modification methods have already been established in this field.
  • the “antibody” in the present invention includes these conjugated antibodies.
  • the cytotoxic T cell induction inhibitor containing the IL-6 inhibitor of the present invention as an active ingredient can be used for suppressing rejection after transplantation.
  • the present invention also provides an inhibitor of rejection in heart transplantation, which contains an IL-6 inhibitor as an active ingredient.
  • the rejection that the inhibitor of the present invention suppresses is not particularly limited, but is preferably an actual Acute rejection is a problem in transplantation medicine.
  • This rejection refers to allografts that are recognized as foreign antigens due to differences in the major histocompatibility complex (MHC) that regulates histocompatibility, and the recipient's cells. It is a pathological condition in which the acroft is attacked by the activity of cytotoxic T cells and helper T cells. It usually appears within 3 months after transplantation, but it may be diagnosed as cell infiltration into the allograft tissue after 3 months.
  • MHC major histocompatibility complex
  • suppression of rejection after transplantation means to improve the survival rate by suppressing damage to the transplanted organ.
  • organ transplantation in which the inhibitor of the present invention is used, organ transplantation is not particularly limited.
  • organ transplants targeted by the present invention include parenchymal organs such as heart, liver, kidney, spleen, lung, and small intestine, and further to tissue transplants such as heart valve, blood vessel, skin, bone, cornea and the like. Is also applicable.
  • Confirmation of the ability to suppress rejection after transplantation can be performed by measuring the CTL activity in the subject after administering the inhibitor of the present invention, as described in the Examples. .
  • the inhibitor of the present invention when a continuous decrease in the CTL activity of the recipient against the donor's HLA antigen appears, it can be considered that the transplantation disorder has been suppressed.
  • the survival of the organ can be determined by whether or not the function of each organ becomes normal after transplantation.
  • the IL-6 signaling inhibitory activity of the IL-6 inhibitor used in the present invention can be evaluated by a commonly used method. Specifically, an IL-6-dependent human myeloma line (S6B45, KPM M2), a human Rennelt T lymphoma cell line KT3, or an IL-6-dependent cell MH60.BSF2 is cultivated and IL-6 is added thereto. At the same time, IL-6-dependent cells can be measured for 3H-thymidine incorporation by coexisting with an IL-6 inhibitor.
  • the 1251-labeled cell bound to the IL-6 receptor-expressing cell Measure IL-6.
  • the 1251-labeled cell bound to the IL-6 receptor-expressing cell Measure IL-6.
  • a negative control group that does not contain an IL-6 inhibitor, and the results obtained from both are compared. 6 Inhibitory activity can be evaluated.
  • the subject to which the inhibitor of the present invention is administered is a mammal.
  • the mammal is preferably a human.
  • the inhibitor of the present invention can be administered in the form of a pharmaceutical, and can be administered systemically or locally orally or parenterally.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, suppository, enema, oral intestinal solvent, etc. can be selected, and the administration method should be selected appropriately depending on the age and symptoms of the patient.
  • Effective doses are selected in the range of O.Olmg to lOOmg per kg body weight. Alternatively, a dose of 1 to 1000 mg, preferably 5 to 50 mg per patient can be selected.
  • an effective dose is an effective dose that is such that free antibody is present in the blood.
  • 0.5 mg to 40 mg preferably 1 mg to 20 mg, once a month (4 weeks), divided into several doses, for example, twice a week, once a week, once a week, once a week Z2, once a week Z4
  • Intravenous injection such as intravenous drip, subcutaneous injection, etc., according to the schedule.
  • the dosing schedule is 2 times Z week or 1 time Z week to 1 time Z 2 weeks, 1 time Z 3 weeks, 1 time Z 4 weeks while observing the state after transplantation and observing the trend of blood test values. It is also possible to make adjustments such as extending the length.
  • a pharmaceutically acceptable carrier such as a preservative and a stabilizer may be added to the inhibitor.
  • the pharmaceutically acceptable carrier may be a material that itself has an inhibitory effect on the induction of cytotoxic T cells, or may be a material that does not have the inhibitory effect. Means a material that can be administered with other inhibitors. In addition, even a material that does not have an inhibitory effect on the induction of cytotoxic T cells has a synergistic or additive stability effect when used in combination with an IL-6 inhibitor. Moyo.
  • Examples of the materials acceptable for pharmaceutical preparations include sterilized water, physiological saline, stabilizers, excipients, buffers, preservatives, surfactants, chelating agents (EDTA, etc.), binders and the like. be able to
  • examples of the surfactant include nonionic surfactants, such as sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate; Caprylate, glycerin monomyristate Glycerin fatty acid esters such as glyceryl monostearate; polyglycerin fatty acid esters such as decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate; polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan mono Polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan tristearate; polyoxyethylene sorbitan tetrastearate Polyoxyethylene sorbite fatty acid ester such as polyoxyethylene
  • the surfactant also include an anionic surfactant, for example, an alkyl sulfate having an alkyl group having 10 to 18 carbon atoms such as cetyl sodium sulfate, sodium lauryl sulfate, sodium oleyl sulfate, etc .; polyoxyethylene Polyoxyethylene alkyl ether sulfates having an average addition mole number of ethylene oxide of 2 to 4 and an alkyl group having 10 to 18 carbon atoms such as sodium lauryl sulfate; alkyl groups such as ester sodium lauryl sulfosuccinate Alkylsulfosuccinic acid ester salts having 8 to 18 carbon atoms; natural surfactants such as lecithin, glyce mouth phospholipids; sphingophospholipids such as sphingomyelin; sucrose fatty acids having 12 to 18 carbon atoms Esters etc.
  • an anionic surfactant for example, an alkyl sulfate
  • surfactants can be added in combination to the inhibitor of the present invention.
  • Preferred surfactants for use in the formulations of the present invention are polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, 40, 60 or 80, with polysonolates 20 and 80 being particularly preferred.
  • polyoxyethylene polyoxypropylene glycol represented by poloxamer such as Pull Knick F-68 (registered trademark) is also preferable.
  • the amount of surfactant added varies depending on the type of surfactant used.
  • polysorbate 20 or polysorbate 80 it is generally 0.001 to 100 mg / mL, preferably 0.003 to 50 mg / mL. Preferably it is 0.005 to 2 mg / mL.
  • phosphoric acid As a buffering agent, phosphoric acid, citrate buffer, acetic acid, malic acid, tartaric acid, succinic acid, lactic acid, potassium phosphate, darconic acid, strong prillic acid, deoxycholic acid, salicylate
  • examples thereof include other organic acids such as acid, triethanolamine, and fumaric acid, and carbonate buffer, tris buffer, histidine buffer, and imidazole buffer.
  • a solution preparation may be prepared by dissolving in an aqueous buffer known in the field of solution preparations.
  • concentration of the buffer is generally 1 to 500 mM, preferably 5 to 100 mM, and more preferably 10 to 20 mM.
  • the inhibitor of the present invention includes other low molecular weight polypeptides, proteins such as serum albumin, gelatin and immunoglobulin, saccharides such as amino acids, polysaccharides and monosaccharides, carbohydrates, and sugar alcohols.
  • proteins such as serum albumin, gelatin and immunoglobulin
  • saccharides such as amino acids, polysaccharides and monosaccharides, carbohydrates, and sugar alcohols.
  • the amino acid is a basic amino acid such as arginine, lysine, histidine, ortin and the like, or an inorganic salt of these amino acids (preferably in the form of hydrochloride or phosphate, ie, phosphate. Amino acid).
  • the preferred pH value is determined by appropriate physiologically acceptable buffer substances such as inorganic acids, especially hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid or their salts. Adjusted. In this case, the use of phosphate is particularly advantageous in that a stable lyophilizate is obtained.
  • the preparation is substantially free of organic acids such as malic acid, tartaric acid, citrate, succinic acid, fumaric acid, etc. or the corresponding anions (malate ion, tartrate ion, citrate ion, This is particularly advantageous in the absence of succinate ions, fumarate ions, etc.
  • Preferred amino acids are arginine, lysine, histidine or ortin.
  • acidic amino acids such as glutamic acid and aspartic acid, and their salt forms (preferably sodium salts) or neutral amino acids such as isoleucine, leucine, glycine, serine, threonine, parin, methionine, cysteine, or alanine, or Aromatic amino acids such as ferulalanin, tyrosine, tryptophan, or the derivative N-acetyl tryptophan can be used.
  • saccharides and carbohydrates such as polysaccharides and monosaccharides include dextran, gnolecose, fructose, ratatose, xylose, mannose, manolethose, sucrose, trehalose, and raffinose.
  • examples of sugar alcohols include mannitol, sorbitol, inositol, and the like.
  • aqueous solution for injection for example, physiological saline, glucose and other adjuvants (for example, D-sorbitol, D-mannose, D-manntol, sodium chloride)
  • physiological saline, glucose and other adjuvants for example, D-sorbitol, D-mannose, D-manntol, sodium chloride
  • an isotonic solution containing The aqueous solution may be used in combination with an appropriate solubilizing agent (eg, alcohol (ethanol, etc.), polyalcohol (propylene glycol, PEG, etc.), nonionic surfactant (polysorbate 80, HCO-50, etc.).
  • solubilizing agent eg, alcohol (ethanol, etc.), polyalcohol (propylene glycol, PEG, etc.), nonionic surfactant (polysorbate 80, HCO-50, etc.
  • it may further contain a diluent, a solubilizing agent, a pH adjuster, a soothing agent, a sulfur-containing reducing agent, an antioxidant, and the like.
  • examples of the sulfur-containing reducing agent include N-acetyl cysteine, N-acetyl homocystine, thiotate, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycol.
  • examples thereof include acids and salts thereof, sodium thiosulfate, glutathione, and those having a sulfhydryl group such as thioalkanoic acid having 1 to 7 carbon atoms.
  • antioxidant for example, erythorbic acid, dibutylhydroxytoluene, butylhydroxyl-sol, -tocopherol, tocopherol acetate, L-ascorbic acid and its salt, L- Ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, triamyl gallate, gallic
  • antioxidants for example, erythorbic acid, dibutylhydroxytoluene, butylhydroxyl-sol, -tocopherol, tocopherol acetate, L-ascorbic acid and its salt, L- Ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, triamyl gallate, gallic
  • chelating agents such as propyl benzoate, disodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.
  • microcapsules such as hydroxymethylcellulose, gelatin, and poly (methacrylic acid)
  • colloid drug delivery systems ribosomes, albumin microspheres, microemulsions, nano Particle and nano force psenore etc.
  • a method of making a drug a sustained-release drug is also known and can be applied to the present invention (Langer et al., J. Biomed. Mater. Res. 1981, 15: 167-277; Langer, Chem. Tech. 1982, 12: 98-105; U.S. Patent 3,773,919; European Patent Application Publication (EP) 58,481; Sidman et al., Biopolymers 1983, 22: 547-556; EP ⁇ 133,988 ⁇ -) 0
  • the pharmaceutically acceptable carrier to be used is appropriately or in combination selected from the above depending on the dosage form, but is not limited thereto.
  • the present invention relates to a method for suppressing rejection after transplantation, comprising a step of administering an IL-6 inhibitor to a subject.
  • the present invention also relates to a method for suppressing rejection in heart transplantation, comprising a step of administering an IL-6 inhibitor to a subject.
  • the rejection suppressed by the method of the present invention is not particularly limited, but is preferably acute rejection.
  • organ transplantation is not particularly limited in organ transplantation in which the inhibitor of the present invention is used.
  • organ transplants targeted by the present invention include parenchymal organs such as heart, liver, kidney, spleen, lung and small intestine, and tissues such as heart valve, blood vessel, skin, bone and cornea. It can also be applied to transplantation.
  • the "subject” refers to an organism to which the IL-6 inhibitor of the present invention is administered and a part of the organism.
  • Organisms include, but are not limited to, animals (eg, humans, domestic animal species, wild animals).
  • the “part of the living body” is not particularly limited.
  • administering includes oral or parenteral administration.
  • Oral administration can include administration in the form of oral preparations, and oral dosage forms include granules, powders, tablets, capsules, solvents, emulsions, and suspensions. Can be selected.
  • Parenteral administration can include injections and! /, In the form of a tube, and injections include subcutaneous injections, intramuscular injections, intraperitoneal injections, and the like. be able to.
  • the effect of the method of the present invention can be achieved by introducing a gene containing an oligonucleotide to be administered into a living body using a gene therapy technique.
  • the agent of the present invention can be locally administered to a region where treatment is desired.
  • administration can be by local injection during surgery, use of a catheter, or targeted gene delivery of DNA encoding a peptide of the invention.
  • Administration of the inhibitor of the present invention to a subject may be before organ transplantation, at the same time as organ transplantation, or after organ transplantation.
  • the inhibitor may be administered once or continuously.
  • the inhibitor of the present invention when administering to a part of an organism extracted or excreted from an organism, the inhibitor of the present invention may be "contacted" with a part of the organism.
  • contact is performed according to the state of the organism.
  • it is not limited to these methods that can include application of the inhibitor to a part of the organism, addition of the inhibitor to a part of the organism, and the like.
  • the inhibitor is added to the culture medium of the cell, or the DNA containing the oligonucleotide of the present invention is introduced into the cell constituting the part of the organism.
  • the above “contact” it is possible to perform the above “contact”.
  • the agents of this invention may be administered as part of a pharmaceutical composition with at least one known chemotherapeutic agent.
  • the agents of the present invention may be administered concurrently with at least one known immunosuppressive agent.
  • the inhibitor of the present invention and the known chemotherapeutic agent may be administered substantially simultaneously.
  • the cytotoxic T cell induction inhibitor of the present invention may be administered to the site where the organ is transplanted after organ transplantation, or may be administered to the target simultaneously with the organ. Good. Further, it may be administered in vitro to an organ before transplantation.
  • P815 mastocytoma cells were intraperitoneally administered to C57BL / 6 mice. After 13 days, spleens were collected from these mice, and spleen cells (effector cells) were cultured with 51Cr-labeled P815 cells (target cells) at various effector / target cell (E / T) ratios. CTL activity against P815 was measured.
  • CTL activity was measured by measuring the cell lysis rate in each cell.
  • the dissolution rate of the cells was expressed as [(51Cr release amount in experiment-spontaneous 51Cr release amount) Z (total 51Cr release amount-spontaneous 51Cr release amount)] X100.
  • an anti-IL-6 receptor antibody (MR16-1) was intraperitoneally administered 2000 mg 4 days before the alloantigen administration, 500 mg intraperitoneally 1 day before, and 4 days and 9 days after the alloantigen administration. 500 mg was administered, and CTL activity was measured by the method described above.
  • Lag HgG was administered to control mice as a control antibody against IL-6 receptor antibody under the same treatment conditions, and CTL activity was measured by the method described above.
  • mice treated with anti-IL-6 receptor antibody showed statistically significant allogeneic antigen (P815) compared with mice not treated with antibody and mice treated with control antibody.
  • P815 decreased CTL activity against mastocytoma (Figs. 1 and 2).
  • P 0.01 Inoculation of IL-6-deficient C57BL / 6 mice with P815 cells revealed that CTL induction in vivo was significantly reduced (data not shown). .
  • EL4 lymphoma cells intraperitoneally administered to BALB / c mice. After 13 days, the spleen was removed from these mice, and spleen cells (effector cells) were cultured with 5 lCr-labeled EL4 cells (target cells) at various effector / target cell (E / T) ratios.
  • CTL activity against EL4 was measured by the method described in Example 1.
  • the anti-IL-6 receptor antibody was administered intraperitoneally 2000 mg 4 days before the alloantigen administration, 500 mg intraperitoneally 1 day before, and administered 500 mg 4 days and 9 days after the alloantigen administration. Then, CTL activity was measured by the method described above.
  • Lag HgG was administered to control mice under the same treatment conditions as a control antibody against IL-6 receptor antibody, and CTL activity was measured by the method described above.
  • mice treated with anti-IL-6 receptor antibody showed statistically significant allogeneic antigen (EL4) compared to mice not treated with antibody and mice treated with control antibody. Decreased CTL activity against lymphoma (Figs. 3 and 4). (P 0.01)
  • anti-IL-6 receptor antibody retains the function of suppressing the induction of cytotoxic T cells!
  • mice used for the experiment were purchased from Japan SLC Co., Ltd., bred in the Animal Experiments Division, Life Sciences, Shinshu University Human Environmental Science Support Center, and bred according to the animal experiment protocol of our facility.
  • a BALB / c mouse as a donor and an allogeneic C57BL / 6 mouse as a recipient
  • a mouse ectopic heart transplant model was prepared by microscopic surgery according to the following procedure. Donors and recipients were 4-8 week old male mice.
  • Both donor and recipient mice were anesthetized by intraperitoneal injection of 70 mg / kg of Pentobarbital sodium (Nenbutal®) 70 mg / kg.
  • the transplanted heart was left with the ascending artery used for anastomosis and the pulmonary artery, and the other blood vessels were ligated together and removed.
  • the transplanted heart was stored in 7.5% cold saline with parin added to ice.
  • the recipient laparotomies in the midline, the intestinal tract was dislocated to expose the abdominal aorta and inferior vena cava, and after blocking the blood flow with microclips for microvessels, each surface was incised approximately 1 mm to make an anastomosis It was created.
  • the aorta of the transplanted heart and the recipient's abdominal aorta, the pulmonary artery of the transplanted heart and the inferior vena cava of the recipient were anastomosed with continuous sutures of 10-0 nylon thread.
  • the microclip was gradually released, blood flow was resumed, and resumption of the heartbeat of the transplanted heart was confirmed. After confirming hemostasis, suture the abdominal wall and skin And closed.
  • the duration of one operation was approximately 45 minutes and the success rate was over 95%.
  • the treatment group was injected intraperitoneally with anti-IL-6 receptor antibody at a dose of 2 mg / mouse / dose immediately after surgery, 3 days and 6 days later.
  • the pulsation of the transplanted heart was confirmed daily by palpation of the abdomen, and cessation of complete pulsation was rejected. At that time, the recipient was anesthetized after anesthesia and the pulsation was confirmed macroscopically. The number of days until refusal was compared as the survival period of the transplanted heart.
  • Untreated group 7, 7, 7, 7, 7, 7, 8, 9, 9, 9, 10 (0). (11 cases, median survival time: 7 days).
  • Anti-IL-6 receptor antibody treatment group 11, 13, 16, 17, 20, 21 (day). (6 cases, median survival time: 1 6.5 days).
  • a histopathological section was prepared from a frozen tissue specimen of the transplanted heart 5 days after transplantation, and stained with hematoxylin and eosin. In the untreated group, extensive inflammatory cell infiltration and myocardial necrosis were observed. In the anti-IL-6 receptor antibody treatment group, inflammatory cell infiltration was only mild, and the myocardial cell structure was relatively maintained (Fig. 6).

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Abstract

Selon l'invention, suite à l'examen de l'effet inhibiteur d'un anticorps des récepteurs anti-IL-6 sur l'induction des cellules T cytotoxiques, une souris traitée avec l'anticorps des récepteurs anti-IL-6 manifeste une diminution statistiquement significative de l'activité cytotoxique des cellules T vis-à-vis d'un alloantigène par rapport à une souris non traitée avec l'anticorps ou à une souris traitée avec un anticorps témoin. En outre, après administration d'un anticorps des récepteurs anti-IL-6 à un receveur de transplantation cardiaque dans un modèle de souris allogène, l'infiltration de cellules inflammatoires vers le cœur transplanté est histopathologiquement inhibée et la survie du greffon du cœur transplanté est significativement prolongée. En d'autres termes, les inventeurs ont découvert pour la première fois que l'induction de cellules T cytotoxiques est inhibée par l'administration de l'anticorps des récepteurs anti-IL-6 et que l'on peut inhiber la réponse aiguë de rejet après transplantation.
PCT/JP2006/322726 2005-11-15 2006-11-15 Inhibiteur de l'induction des cellules t cytotoxiques Ceased WO2007058194A1 (fr)

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US12/085,065 US8623355B2 (en) 2005-11-15 2006-11-15 Methods for suppressing acute rejection of a heart transplant
KR1020087014199A KR101457709B1 (ko) 2005-11-15 2006-11-15 세포 상해성 ｔ 세포의 유도 억제제
JP2007545256A JP5189366B2 (ja) 2005-11-15 2006-11-15 細胞傷害性ｔ細胞の誘導抑制剤
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